Throughout this application various publications are referred to in parenthesis. Citations for these references may be found at the end of the specification preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
Infantile spasm syndrome, or infantile spasms (IS), represents an age-related epileptic syndrome characterized by brief spasms, specific EEG patterns [hypsarrhythmia (interictally) and electrodecremental responses (ictally)], with frequent subsequent cognitive deterioration. The incidence of IS is 2.5 per 10,000 live births (Bobo et al., 1994; Hrachovy and Frost, 2003) with a slight (60%) male predominance (Webb et al., 1996). The causes of IS are diverse and can be multifactorial, often a combination of genetic predisposition (Mizukawa et al., 1992; Bingham et al., 1996; Dulac et al., 1993a) and environmental insults (Watanabe, 1998). IS can be classified into symptomatic, cryptogenic and idiopathic groups (Id.). Symptomatic IS are considered the consequence of a known CNS disorder and comprise the largest proportion of cases (Hrachovy and Frost, 2003; Watanabe, 1998). IS can occur following multiple etiologies, including brain malformations such as tuberous sclerosis, hypoxic ischemic injury, trauma, toxins and infections, often as a combination of additive insults (Watanabe, 1998; Short et al., 1995; Saktik et al., 2003; Alvarez et al., 1987; Cusmai et al., 1993). The extent of abnormalities can be documented with MRI in vivo or in post mortem examination (Watanabe, 1998, Saltik et al., 2003; Hashimoto et al., 1990). In one recent review, over 200 etiological and associative factors were linked to IS (Hrachovy and Frost, 2003). In the cryptogenic group, a CNS abnormality is suspected but remains unidentified. In the idiopathic group, the cause is unknown and suspected to be genetic. In both idiopathic or cryptogenic IS, the MRI does not show any abnormalities (Watanabe, 1998). After the onset of IS, many patients may begin losing developmental milestones and, subsequently, may become mentally retarded, as the epileptic encephalopathy progresses (Kurokawa et al., 1980; Riikonen, 1982; Riikonen and Amnell, 1981; Koo et al., 1993; Favata et al., 1987). The prognosis is somewhat better in patients with cryptogenic or idiopathic IS (Lombroso, 1983; Pang et al., 2003; Dulac et al., 1993b). In the majority of the cases, IS have their onset between 3-7 months of age and 85% start before one year of age (Jeavons et al., 1973). IS commonly occur during transitions in the sleep wake cycle (Baird, 1959; Druckman and Chao, 1955; Kellaway et al., 1979; King et al., 1985), often in clusters (Kellaway et al., 1979; King et al., 1985; West, 1841; Plouin et al., 1993). They involve flexion of the neck and upper body and adduction of the arm (flexion spasms) (West, 1841) or contractions of the extensor muscles with sudden extension of the neck and trunk with extension and abduction of the limbs (extension spasms) (Caraballo et al., 2003). The ictal EEG pattern consists of an electrodecremental response (Kellaway et al., 1979; Plouin et al., 1993; Maheshwari and Jeavons, 1975). The interictal EEG recordings show a disorganized high voltage background with multifocal spikes called hypsarrhythmia (Gibbs and Gibbs, 1952). It has been suggested that early recognition of IS and institution of early treatment is required to improve outcome (Curatolo, 2005). Unfortunately, IS are not often controlled by conventional AEDs (Haines and Casto, 1994). The most widely accepted treatment is administration of ACTH (Snead et al., 1983; Baram et al., 1996; Mackay et al., 2004), a potentially toxic agent (Satoh et al., 1982). The response to treatment with ACTH is variable ranging from 40 to 100% (Mackay et al., 2004). ACTH is more effective in treating idiopathic/cryptogenic IS than symptomatic IS (Wolf and Moshe, 2002). When effective, ACTH leads to the cessation of spasms although after treatment is stopped, the spasms may recur (Snead et al., 1983; Baram et al., 1996; Mackay et al., 2004; Pollack et al., 1979). Vigabatrin (another potentially toxic agent) is effective in some cases too, especially in IS associated with tuberous sclerosis (Mackay et al., 2004; Lux et al., 2005; Vigevano and Cilio, 1997). Clinical studies show that IS may spontaneously remit between 12-24 months of age (Bachman, 1981; Hrachovy et al., 1991; Dulac et al., 1997). However, the cognitive deficits persist and the children are often mentally retarded (Caplan et al., 2002). Furthermore, new seizure types (including partial seizures without and with secondary generalization) may emerge often intractable to treatment with AEDs (Riikonen, 1982; Jeavons et al., 1973; Jeavons and Bower, 1961; Rantala and Putkonen, 1999). Finally, IS are associated with high mortality rates. Review of the literature suggests that 5-30% of the children with IS die. Of these deaths 50% are disease-related and 50% treatment-related (Riikonen, 1982; Snead et al., 1983; Rantala and Putkonen, 1999; Appleton, 2001; Mackay et al., 2002). Mortality is greater in symptomatic cases (Dulac et al., 1997).
Because IS are associated with dismal outcomes, it is important to develop innovative, effective, non-toxic treatments to promptly stop the seizures and the regression. This will require the identification of a model system to be used to identify new treatments and screen for efficacy in preclinical studies. A successful model would be expected to meet certain minimum criteria outlined at the “Models of Pediatric Epilepsies,” workshop, held in Bethesda, Md. on May 13-14, 2004. The Workshop was sponsored by NIH/NINDS, in conjunction with the American Epilepsy Society and the International League Against Epilepsy and summarized in Stafstrom et al., 2006). The proposed minimum criteria include 1) spontaneous recurrent epileptic spasms that occur within a developmental window corresponding to that seen in humans; 2) the tonic spasms should be associated with cortical EEG electrodecremental discharges; 3) the epileptic spasms should be responsive to some degree to ACTH or vigabatrin treatment; and 4) evidence for behavioral and cognitive sequelae. In addition, another criterion was considered: the cortical interictal EEG should show hypsarrhythmia. Because the definition of hypsarrhythmia includes the presence of multifocal, high amplitude discharges (Gibbs and Gibbs, 1952), this pattern may be extremely difficult to realize in a rat or mouse pup where placement of multiple electrodes in the brain is limited by its size and fragility of skull bones. Therefore, modeling of hypsarrhythmia may be restricted to larger animal models until technological advances permit the development of “micro” electrode assemblies (Stafstrom et al., 2006).
Animal models of the human IS phenotype have been especially difficult to generate. In the NIH/NINDS workshop, the participants discussed various attempts to create such models. One model involves i.c.v. administration of picomolar amounts of corticotrophin releasing hormone (CRH) to neonatal rats (Brunson et al., 2001b), an interesting approach given the peculiar response of IS to ACTH. Further, the perinatal stress caused by etiologies associated with IS has led to the hypothesis that stress may increase endogenous CRH levels in seizure-prone areas of the developing brain, leading to neuronal damage, axonal reorganization and long-term cognitive deficits (Avishai-Eliner et al., 2002). However, the consensus was that, although CRH-treated rats display cognitive deficiencies, the CRH-induced seizure phenotype is (primarily “limbic”) and the EEG abnormalities do not mimic features of IS. Moreover and the seizures are not responsive to ACTH; however ACTH does reduce CRH gene expression in certain neuronal populations (Brunson et al., 2001a). Another attempt to model IS involves one i.p. injection of NMDA in infant rats (Kabova et al., 1999; Stafstrom and Sasaki-Adams, 2003). This agent causes a clinical seizure described as ‘emprosthotonus’, consisting of whole-body tonic flexion with back-arching. These seizures are often accompanied by a diffuse attenuation of the EEG amplitude, but without any epileptiform discharges. Furthermore, spontaneous seizures have not been recorded and hormonal pretreatment (with hydrocortisone) does not decrease but instead increases the frequency of the ‘emprosthotonic’ seizures. However, if the pups are prenatally exposed to betamethasone, pretreatment with ACTH, prior to the administration of NMDA, increases the latency to the onset of the ‘emprosthotonic’ seizures. This observation together with the fact that there is no preexisting structural pathology has led to the hypothesis that this may be a model of idiopathic IS (Velisek et al. 2007). Lee et al have also recently reported that intracerebral infusions of tetrodotoxin in rat pups for several weeks starting on the 10th day of life lead to the development of spontaneous recurrent seizures in adulthood (Lee, Frost et al. 2006). The seizures are characterized by frequent head nodding or myclonic jerks involving the whole body; the ictal EEG often shows a slow wave followed by generalized voltage attenuation resembling an electrodecremental discharge. Some rats with seizures also have diffuse EEG multifocal discharges resembling hypsarrythmia. In this model, however, the seizures occur in adulthood. The observation of seizures in adult animals is not consistent with the human data where IS occur early in life.